In 1978, it was reported for the first time that an antisense molecule inhibited influenza virus infection. Since then, reports have been issued that antisense molecules inhibited the expression of oncogenes and AIDS infection. In recent years, antisense oligonucleotides have become one of the most promising pharmaceuticals, because they specifically control the expression of undesirable genes.
The antisense method is based on the idea of controlling a unidirectional flow called the central dogma, i.e., DNA→RNA→protein, by use of an antisense oligonucleotide.
When a naturally occurring oligonucleotide was applied to this method as an antisense molecule, however, it was decomposed with various nucleases in vivo, or its permeation through the cell membrane was not high. To solve these problems, numerous nucleic acid derivatives and analogues have been synthesized, and their studies have been conducted. Examples of the synthesized products include a phosphorothioate having a sulfur atom substituting for an oxygen atom on the phosphorus atom, and a methylphosphonate having a substituting methyl group. Recently, products have been synthesized in which the phosphorus atom has also been substituted by a carbon atom, or the structure of the sugar portion has been changed, or the nucleic acid base has been modified. Any resulting derivatives or analogues, however, have not been fully satisfactory in terms of In vivo stability, ease of synthesis, and sequence specificity (the property of selectively controlling the expression of a particular gene alone).
Under these circumstances, the re has been a demand for the creation of an antisense molecule which is minimally decomposed with a nuclease in vivo, binds to target messenger RNA with high affinity, has high specificity, and can thus efficiently control the expression of a particular gene.